Ectopic expression of interferon-gamma (IFN-gamma) in the lens provides a model for studying the clinical and biological effects of IFN-gamma in the normal development of the eye. In this project, two transgenic mouse lines expressing IFN-gamma under the direction of lens-specific alphaA-crystallin promoter were established using two distinct mouse strains, Balb/c and FVB/N. In both the `ACry-IFN- gamma/Balb/c and alphaACry-IFN-gamma/FVB/N transgenic mice, the essential histopathological features observed were very similar at all developmental stages studied (12- to 18-day embryos, newborns, adults), suggesting that maldevelopment of ocular tissues of these mice resulted from `ACry-IFN-gamma expression. The differentiation of tissues of surface ectodermal, neuroectodermal, and mesodermal origin was adversely affected. In the lens, normal differentiation of the anterior and posterior lens cells was perturbed, resulting in marked disorganization of the entire lens architecture and very little or no lens fiber formation. The retina was very convoluted with retinal detachment, retinal degeneration, partial loss of photoreceptors, and accumulation of intraocular macrophages in the subretinal space. Vitritis, iridocyclitis, and corneal and vitreous neovascularization were commonly observed. To investigate the molecular basis of IFN-gamma-mediated disruption of the normal developmental program of ocular tissues, we analyzed the abundance of mRNA transcripts of several lens genes: alphaA-crystallin, major intrinsic protein (MIP), alphaB-crystallin, macrophage inhibitory factor (MIF), transforming growth factor (TGF~), DNA-binding protein (dbpB/YB-1), and major histocompatibility complex (MHC) class II in `ACry-IFN-gamma mice and age-matched controls. In the transgenic mice, upregulation of MHC class II gene was observed while MIP gene transcription was silenced. Transcription of the other lens genes was not affected. Although the alphaA-crystallin promoter is normally active only in lens tissue, its tissue specificity was abrogated in the alphaACry-IFN-gamma/Balb/c and alphaACry-IFN-gamma/FVB/N transgenic mice; expression of alphaACry-IFN-gamma also was found in the brain, kidney, liver, ovary, spleen, testes, and thymus. Furthermore, upregulation of MHC class II also was found in the brain, kidney, liver, ovary, and testes.